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It’s not the CB1 and CB2 receptors after all

Dog plays on beach

Guess what? It is not the CB1 and CB2 receptors.  Widespread belief is that CBD and CBDA interact with the CB1 and CB2 receptors, but new research from ElleVet shows that that is incorrect.    

Go to any CBD company website and you will find a diagram showing the location of the CB1 and CB2 receptors in the body of a dog or cat and an explanation of how cannabinoids work with these receptor systems. This is incorrect and outdated information. As our research into CBD + CBDA and the other cannabinoid molecules increases, the ElleVet team’s understanding of the mechanism of how CBD interacts with the body is constantly expanding and deepening. This receptor data is groundbreaking, and we use this information to help understand how the body interacts with CBD + CBDA. This information helps us continuously improve and develop new and highly effective products. Read on to hear about how CBD + CBDA work in the body of your pet and which receptors are involved.   

It has been proven that CBD may be an allosteric inhibitor of the CB1 and CB2 receptors, but only at a concentration level that would not be achievable or relevant. Many receptor pharmacology studies have been performed and based on the serum concentrations that can be achieved, it is very unlikely that these receptors play a role. There is a growing consensus that other receptor systems, including transient receptor potential channels, serotonin receptor, g protein orphan receptors (GPR55), glycine receptor, peroxisomal proliferator-activated receptors, and adenosine transport channels may play a far more significant role in the CBD and CBDA response that previously thought. Discomfort mitigation, the anti-inflammatory effect, overall sense of wellness, neuro support, anti-nausea, and anti-vomiting are all regulated by CBD and CBDA interactions with these receptor systems and channels, with CBDA having a key role, particularly in the anti-inflammatory and serotonin response.    

Exactly what do these receptor systems do? It turns out that the receptor systems that are CBD or CBDA targets begin with the transient receptor potential channels, or TRP family of channels. This family of ion channels are affected by CBD because of the high affinity at concentrations that, based on channel pharmacology, are activated and desensitized at what we feel are pharmacologically achievable concentrations based on our pharmacokinetic studies.    

These TRP receptors are important in the peripheral and central nervous systems for detecting discomfort stimuli. The binding of CBD + CBDA to these receptors activates and eventually desensitizes the channels, thereby dampening sensation transmission and perception.     

Other receptor groups, such as the g protein orphan receptors (GPR), glycine, peroxisomal proliferation gamma (PPAR-g), and adenine receptor systems, have historically been poorly studied but have been found to be influenced by CBD and CBDA. GPR55 and glycine are involved in neuronal signaling and depolarization, where GPR55 may regulate depolarization when activated by endogenous cannabinoids. CBD is an antagonist of this receptor. Conversely, when the glycine receptor is activated, it allows for repolarization due to an influx of chloride, causing hyperpolarization of the neuron, which supports physical comfort.     

The PPAR-g receptor is an intracellular receptor that influences transcription and translation of genes that are usually involved in cytokine production in immune cells, leading to global dampening of the inflammatory response in macrophages and histocytes.    

As far as neurological issues, CBD and CBDA seem to interact at the adenosine receptor/equilibrate nucleotide transporter, leading to alterations in glutamatergic signaling and calming neuronal excitability, thereby reducing neuro activity.    

Finally, the 5HT1A receptor and the 5HT3A receptor, which are both serotonin receptors that are influenced by CBD as an agonist to promote both serotonergic stimulus and homeostasis around serotonin signaling, promoting a feeling of happiness and overall wellness. Interestingly, CBDA has a higher affinity for these receptors and has been shown to be even more effective than CBD regarding nausea and appetite.    

Lastly, there is also evidence that CBD and CBDA allow for inhibition of the enzymes that break down the natural ligands to CB1 and CB2 receptors. This may allow for higher synaptic concentrations of these natural ligands, therefore CBD and CBDA may influence CB1 and CB2 receptors through obtuse indirect mechanisms.    

So, all together, the receptor systems relevant to CBD and CBDA are far more varied and complex than previously thought, and do not directly involve the CB1 and CB2 receptor systems at physiologically relevant concentrations. The TRP, GPR, PPAR-g GPR55, 5HT, glycine, and adenosine uptake receptors are all involved in processes involving CBD and CBDA and acting in areas of discomfort mitigation, ant-inflammatory response, neurological regulating, and wellness. 

Additionally, CBD has a greater affinity for some of the TRP channels, while CBDA has greater ability to interact at the 5HT1A and PPAR receptor which makes a blend more useful than a single cannabinoid. CBDA and the other acidic forms, such as CBGA and THCA, appear to have potential as native COX-1 and COX-2 inhibitors. And most importantly, CBDA appears to stimulate the PPAR system, leading to potential decrease in COX enzyme production as part of its effect on inflammation. 

Not only does this insight into the receptor systems allow for a deeper understanding of the mechanism of CBD and CBDA, which can then translate to more effective products, but it highlights the importance of CBDA and the acidic forms of the molecule.